Nitric oxide is produced in mammalian cells from L-arginine by the action of specific nitric oxide synthases (NOSs). These enzymes fall into two distinct classes—constitutive NOS (cNOS) and inducible NOS (iNOS). At the present time, two constitutive NOSs and one inducible NOS have been identified. Of the constitutive NOSs, an endothelial enzyme (ecNOS) is involved with smooth muscle relaxation and the regulation of blood pressure and blood flow, whereas the neuronal enzyme (ncNOS) serves as a neurotransmitter and appears to be involved in the regulation of various biological functions such as cerebral ischaemia. Inducible NOS has been particularly implicated in the pathogenesis of inflammatory diseases. Regulation of these enzymes should therefore offer considerable potential in the treatment of a wide variety of disease states (J. E. Macdonald, Ann. Rep. Med. Chem., 1996, 31, 221-230).
Considerable effort has been expended in efforts to identify compounds that act as specific inhibitors of one or more isoforms of the enzyme nitric oxide synthase. The use of such compounds in therapy has also been widely claimed.
Patent application EP 0 273 658 discloses compounds of formula wherein Ar represents phenyl optionally substituted by halogen, C1 to 4 alkyl, C1 to 3 alkoxy or CF3, or optionally substituted naphthyl; R1 represents amongst other things C5 to 7 cycloalkyl; and R2 and R3 are each independently H or methyl. Said compounds are potent and selective inhibitors of serotonin and norepinephrine uptake and are thereby stated to be useful in the treatment of human diseases such as anxiety, depression and obesity.
The present invention relates to the surprising finding that a group of phenylheteroalkylamine derivatives, including some compounds that are within the generic scope of EP 0 273 658, are inhibitors of the enzyme nitric oxide synthase.